The present invention relates to indoline derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating obesity and other disorders.
It has been recognised that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, xe2x80x9cObesity: Trends and Treatmentsxe2x80x9d, Scrip Reports, PJB Publications Ltd, 1996).
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2. There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Compounds marketed as anti-obesity agents include Orlistat (Reductil(copyright)) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhoea. Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine (Pondimin(copyright)) and dexfenfluramine (Redux(trademark)) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
The non-selective 5-HT2C receptor agonists/partial agonists m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP) have been shown to reduce food intake in rats (G. A. Kennett and G. Curzon, Psychopharmacol., 1988, 96, 93-100; G. A. Kennett, C. T. Dourish and G. Cuzon, Eur. J. Pharmacol., 1987, 141, 429-435) and to accelerate the appearance of the behavioural satiety sequence (S. J. Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377). Recent findings from studies with mCPP in normal human volunteers and obese subjects have also shown decreases in food intake. Thus, a single dose of mCPP decreased food intake in female volunteers (A. E. S. Walsh et al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetite and body weight of obese male and female subjects during subchronic treatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol., 1997, 133, 309-312). The anorectic action of mCPP is absent in 5-HT2C receptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374, 542-546) and is antagonised by the 5-HT2C receptor antagonist SB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36, 609-620). It seems therefore that mCPP decreases food intake via an agonist action at the 5-HT2C receptor.
Other compounds which have been proposed as 5-HT2C receptor agonists for use in the treatment of obesity include the substituted 1-aminoethyl indoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives and tricyclic 1-aminoethylpyrazole derivatives bind to 5-HT2C receptors and may be used in the treatment of obesity. WO-A-98130548 discloses aminoalkylindazole compounds as 5-HT2C agonists for the treatment of CNS diseases and appetite regulation disorders.
It is an object of this invention to provide selective, directly acting 5HT2 receptor ligands for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide directly acting ligands selective for 5-HT2B and/or 5-HT2C receptors, for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide selective, directly acting 5-HT2C receptor ligands, preferably 5-HT2C receptor agonists, for use in therapy and particularly for use as anti-obesity agents.
According to the present invention there is provided for use in therapy a chemical compound of formula (I): 
wherein:
R1 to R3 are independently selected from hydrogen and alkyl;
R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylanrinocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, arninocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, wherein at least one of R4 to R7 is a substituent group other than hydrogen, and pharmaceutically acceptable salts and prodrugs thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5, C6 or C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl), more preferably methyl.
As used herein, the term xe2x80x9clower alkylxe2x80x9d means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, faranyl and thienyl.
As used herein the term xe2x80x9cheterocyclylxe2x80x9d means a saturated 4, 5, 6 or 7-membered ring preferably a 5 or 6-membered ring) containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) selected from O, S and N (preferably from O and N).
The alkyl, aryl and heterocyclyl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:
carbon-containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted
and unsubstituted benzyl);
halogen atoms and halogen-containing groups such as
oxygen-containing groups such as
nitrogen-containing groups such as
sulfur-containing groups such as
thiols, thioethers, sulfoxides and sulfones
(e.g. alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylthioalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, arylthio, arylsulfinyl,
arylsulfonyl, arylthioalkyl, arylsulfinylalkyl,
arylsulfonylalkyl);
and heterocyclic groups containing one or more, preferably one, heteroatom,
(e.g. thienyl, furanyl, pyrrolyl, imidazolyl,
pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl,
pyrrolidinyl, pyrrolinyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, tetrahydrofuranyl,
pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl,
piperidyl, hexahydroazepinyl, piperazinyl,
morpholinyl, thianaphthyl, benzofuranyl,
isobenzofuranyl, indolyl, oxyindolyl, isoindolyl,
indazolyl, indolinyl, 7-azaindolyl, benzopyranyl,
coumarinyl, isocoumarinyl, quinolinyl,
isoquinolinyl, naphthridinyl, cinnolinyl,
quinazolinyl, pyridopyridyl, benzoxazinyl,
quinoxalinyl, chromenyl, chromanyl,
isochromanyl, phthalazinyl and carbolinyl).
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94 and xe2x80x9calkoylxe2x80x9d means alkyl-COxe2x80x94. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
As used herein the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of the compound of formula (I).
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, suliric and methanesulfonic acids. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
Preferably, the compounds of formula (I) are selected from compounds in which R1 is the same as R2. Preferably, R1 and R2 are both hydrogen. In an embodiment of the invention, R1 is hydrogen and R2 is substituted or unsubtituted alkyl, preferably lower alkyl, preferably methyl. Where substituted, the substituent group is preferably an aryl group, preferably phenyl, pyridyl or thienyl.
Preferably, the compounds of formula (I) are selected from compounds in which R3 is alkyl, preferably lower alkyl, preferably methyl. Where R3 is alky, the carbon atom to which R3 is attached is an asymmetric carbon atom. It is preferred that this asymmetric carbon atom is in the (S)-configuration, wherein the stereochemical assignment is defined with respect to a compound wherein R3 is an unsubstituted alkyl group.
R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, heterocyclyl (including aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, hexahydroazepinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, tetrahydrothienyl and tetrahydrothiopyranyl), alkoxy (including arylalkoxy), aryloxy, alkylthio, arylthio, alkylsulfoxyl, alkylsulfonyl, arylsulfoxyl, arylsulfonyl, amino, monoalkylamino, dialkylamino, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylarninocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino, wherein at least one of R4 to R7 is other than hydrogen.
In an embodiment of the invention R4 to R7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl, wherein at least one of R4 to R7 is other than hydrogen.
It is preferred that the compounds of formula (I) are selected from compounds in which R4 is selected from halogen (preferably fluoro) and hydrogen. R4 is preferably hydrogen.
It is preferred that the compounds of formula (I) are selected from compounds in which R5 is selected from halogen, alkyl, aryl, alkoxy, alkylthio, monoalkylamino and dialkylamino. Preferably R5 is selected from halogen, alkyl, alkoxy, alkylthio, monoalkylamino and dialkylamino, and more preferably from halogen (preferably chloro, bromo and fluoro, more preferably chloro and bromo), alkyl (preferably haloalkyl and more preferably trifluoromethyl), alkoxy (preferably lower alkoxy) and alkylthio (preferably lower alkylthio).
It is preferred that the compounds of formula (I) are selected from compounds in which R6 is selected from halogen and hydrogen. Preferably R6 is selected from halogen (preferably fluoro, chloro and bromo, and more preferably fluoro).
It is preferred that the compounds of formula (I) are selected from compounds in which R7 is hydrogen.
In a preferred embodiment, the compounds of formula (I) are selected from 1-(6-chloro-5-fluoroindol-1-yl)-2-propylarnine, 1-(5,6-difluoroindolin-1-yl)-2-propylamine, 1-(6-bromo-5-fluoroindolin-1-yl)-2-propylamine, 1-(6-bromoindolin-1-yl)-2-propylamine, 1-(6-chloroindolin-1-yl)-2-propylamine, 1-(5-fluoro-6-trifluoromethylindolin-1-yl)-2-propylamine, 1-(5-fluoro-6-methylthioindolin-1-yl)-2-propylamine, 1-(5-fluoro-6-iodoindolin-1-yl)-2-propylamine, 1-(5-fluoro-6-ethylthioindolin-1-yl)-2-propylamine, 1-(-5-fluoro-6-methylindolin-1-yl)-2-propylamine, 1-(6-methylthioindolin-1-yl)-2-propylamine, 1-(6-ethylthioindolin-1-yl)-2-propylamine, 1-(6-trifluoromethylindolin-1-yl)-2-propylamine, 1-(6-methoxyindolin-1-yl)-2-propylamine, 1-(6-propylthioindolin-1-yl)-2-propylamine, 1-(6-isopropylthioindolin-1-yl)-2-propylamine, 2-(6-chloroindolin-1-yl)-1-ethylamine, 2-(6-bromoindolin-1-yl)-1-ethylamine, 1-(5-chloroindolin-1-yl)2-propylamine, 1-(5-fluoroindolin-1-yl)-2-propylamine and 1-(6-methylindolin-1-yl)-2-propylamine, and particularly the (S)-enantiomers thereof.
The compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. The compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
In a preferred embodiment of the invention, a compound of formula (I) is in the form of its (S)-enantiomer, substantially free of its (R)-enantiomer. As used herein, the term xe2x80x9csubstantially free of its (R)-enantiomerxe2x80x9d means that a composition comprising a compound of formula (I) contains a greater proportion of the (S)-enantiomer of the compound of formula (I) in relation to the (R)-enantiomer of the compound of formula (I). In a preferred embodiment of the present invention, the term xe2x80x9csubstantially free of its (R)-enantiomerxe2x80x9d, as used herein, means that the composition contains at least 90% by weight of the (S)-enantiomer and 10% by weight or less of the (R)-enantiomer. In a further preferred embodiment, the term xe2x80x9csubstantially free of its (R)-enantiomerxe2x80x9d means that the composition contains at least 99% by weight of the (S)-enantiomer and 1% or less of the (R)-enantiomer. In another preferred embodiment, the term xe2x80x9csubstantially free of its (R)-enantiomerxe2x80x9d means that the composition contains 100% by weight of the (S)-enantiomer. The above percentages are based on the total amount of a compound of formula (I) present in the composition.
According to a further aspect of the invention, there is provided a compound of formula (I), per se, wherein R7 is a substituent other than hydroxy. In a preferred embodiment, there is provided a compound of formula (I), per se, wherein R7 is hydrogen.
The compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2 receptor function. The compounds may act as receptor agonists or antagonists. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2B and/or 5-HT2C receptor function. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders where a 5-HT2C receptor agonist is required.
The compounds of formula (I) may be used in the treatment or prevention of central nervous disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa or premenstrual tension; damage of the central nervous system such as by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases such as encephalitis or meningitis; cardiovascular disorders such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus; and sleep apnea.
According to a further aspect of the invention, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of the above-mentioned disorders. In a preferred embodiment, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a method of treatment (including prophylaxis) of a disorder selected from the group consisting of the above-mentioned disorders comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I). In a preferred embodiment, there is provided a method of treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
According to a further aspect of the invention, there is provided a method of preparing a compound of formula (I).
Compounds of formula (I) may be prepared according to Reaction Scheme 1 below. R1 to R7 are as previously defined. The (indolyl)-alkylethanol (III) may be prepared by reaction of the substituted indole (II) with an alkylene oxide in the presence of a strong base such as sodium hydride in a solvent such as tetrahydrofuran. The corresponding azido derivative (V) can be formed in a two step procedure from the derivative (III) by formation of the mesylate (IV), obtained by reaction of (III) with methanesulfonyl chloride in the presence of a base such as triethylamine, and subsequent treatment of the mesylate (IV) with sodium azide in a solvent such as dimethyl formamide. The indoline (VI) can then be obtained by reduction of the indole (V) with, for example, sodium cyanoborohydride in acetic acid as solvent. The resultant azidoindoline (VI) can then be reduced to a compound of formula (I) (R1=R2=H) using for example a mixture of zinc powder and nickel chloride hexahydrate in a solvent such as tetrahydrofuran or alternatively using hydrogen over a catalyst such as platinum(IV)oxide in a solvent such as ethanol. 
Alternatively compounds of the invention may be prepared according to Reaction Scheme 2 below. The carbamate (VII) may be formed by reaction of the indole (II) with a carbamoylethylsulfonate in the presence of a strong base such as potassium hydroxide in a solvent such as methyl sulfoxide. The indoline (VIII) may be obtained by reaction of the indole (VII) with a reducing agent such as sodium cyanoborohydride or a tetra-alkylammonium borohydride. The compounds of formula (I) (R1=R2=H) may be prepared by deprotection of the amine function of the indoline (VIII). 
If, in any of the other processes mentioned herein, the substituent group R4, R5, R6 or R7 is other than the one required, the substituent group may be converted to the desired substituent by known methods. The substituents R4, R5, R6 or R7 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
The compounds of formula (I) (R1 and/or R2=alkyl) may be prepared from compounds of formula (I) (R1=R2=H) by standard methods such as reductive alkylation with an appropriate aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride, formic acid or sodium cyanoborohydride.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifiing a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
The compositions comprising a compound of formula (I) may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of formula (I) may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of formula (I) may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The active compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of formula (I) are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of formula (I) for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., obesity) is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.